Despite having more severe obstructive hypertrophic cardiomyopathy (HCM), women treated with mavacamten versus placebo in EXPLORER-HCM showed similar improvements in the primary and most secondary endpoints as men but greater changes in health status and NT-proBNP.

This summary is based on the publication of Cresci S, Bach RG, Saber S, et al. - Effect of Mavacamten in Women Compared With Men With Obstructive Hypertrophic Cardiomyopathy: Insights From EXPLORER-HCM. Circulation. 2023 Nov 14. doi: 10.1161/CIRCULATIONAHA.123.065600

Introduction and methods

Background

Women with hypertrophic cardiomyopathy (HCM) have worse symptoms, a higher incidence and greater severity of HF, and worse outcomes compared with men [1,2]. The EXPLORER-HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy) trial showed that mavacamten, a selective and reversible cardiac myosin ATPase inhibitor, reduced clinical and echocardiographic features of obstructive HCM and improved exercise capacity and health status compared with placebo [3,4].

Aim of the study

In a prespecified post-hoc analysis of the EXPLORER-HCM trial, the authors compared baseline clinical and echocardiographic characteristics and response to mavacamten versus placebo between women and men with obstructive HCM.

Methods

The EXPLORER-HCM trial was a multinational, double-blind, placebo-controlled, phase 3 RCT in which 251 patients with symptomatic obstructive HCM were randomized to mavacamten (starting dose: 5 mg) or placebo for 30 weeks. In this prespecified subgroup and additional post-hoc analyses, all 102 women and 149 men were included.

Outcomes

The prespecified primary endpoint was a composite outcome of either ≥1.5–mL/kg/min increase in peak oxygen consumption (pVO₂) and NYHA class improvement ≥1 or ≥3.0–mL/kg/min increase in pVO₂ with no worsening of NYHA class. Prespecified secondary endpoints were changes in postexercise left ventricular outflow tract (LVOT) gradient, pVO₂, and patient-reported health status (KCCQ – Clinical Summary Score (KCCQ-CSS) and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness of Breath (HCMSQ-SoB) subscore), as well as proportion of patients achieving NYHA class improvement ≥1. The prespecified exploratory endpoint was change in NT-proBNP level. Echocardiographic parameters included LVEF and resting and Valsalva-induced LVOT gradients.

Main results

Baseline characteristics

• At baseline, female patients were older compared with their male counterparts (mean age: 62.0 vs. 56.1 years; P<0.0001), had a lower mean pVO₂ (16.7 vs. 21.3 mL/kg/min; P<0.0001), were more likely to have NYHA class III HF symptoms (42% vs. 17%; P<0.0001), had poorer health status (mean KCCQ-CSS: 64 vs. 75; P<0.0001), had more shortness of breath (mean HCMSQ-SoB: 5.4 vs. 4.1; P=0.0016), and had a higher mean plasma NT-proBNP level (1704 vs. 990 ng/L; P=0.004).

Prespecified endpoints

• After 30 weeks of mavacamten treatment, similar percentages of women and men showed a positive response for the primary composite endpoint of pVO₂ increase (with or with no NYHA class improvement). The mean percentage differences on mavacamten versus placebo were 22% (95%CI: 7%–38%) and 19% (95%CI: 4%–34%), respectively (P for interaction=0.759).
• Women and men also displayed similar changes from baseline in postexercise LVOT gradient (mean difference on mavacamten–placebo: –42.4 vs. –33.6 mmHg; P for interaction=0.348), pVO₂ (1.2 vs. 1.6 mL/kg/min; P for interaction=0.633), and HCMSQ-SoB subscore (–2.3 vs. –1.5; P for interaction=0.305), and comparable proportions of patients achieved NYHA class improvement ≥1 (41% vs. 28%; P for interaction=0.254).
• However, women demonstrated a greater improvement in KCCQ-CSS (mean difference on mavacamten–placebo: 14.8 vs. 6.1; P for interaction=0.026) and a larger NT-proBNP reduction (–1322 vs. –649 ng/L; P for interaction=0.0008) compared with men.

Echocardiographic parameters

• Women showed a lower decrease in LVEF from baseline compared with men (mean difference on mavacamten–placebo: –2.2 vs. –5.6; P for interaction=0.049). For the other echocardiographic measures, no significant interactions between sex and response to mavacamten were observed.

Conclusion

This prespecified post-hoc analysis of the EXPLORER-HCM trial showed that women with symptomatic obstructive HCM were older at baseline and had worse HF, poorer health status, and higher NT-pro-BNP levels compared with men. There were no sex differences in the response to 30-week treatment with mavacamten versus placebo for the primary composite endpoint of pVO₂ increase (with or with no NYHA class improvement) and most secondary endpoints. However, women showed greater improvement in health status as assessed by the KCCQ-CSS and a larger NT-proBNP reduction.

The authors conclude that their “findings have important implications for understanding sex-related differences in the clinical expression of HCM and support patient selection criteria inclusive of women with severe [obstructive] HCM when considering mavacamten treatment.”

References

1. Geske JB, Ong KC, Siontis KC, Hebl VB, Ackerman MJ, Hodge DO, Miller VM, Nishimura RA, Oh JK, Schaff HV, et al. Women with hypertrophic cardiomyopathy have worse survival. Eur Heart J. 2017;38:3434–3440. doi: 10.1093/eurheartj/ehx527
2. Lee HJ, Kim HK, Lee SC, Ommen SR, Kim J, Park JB, Choi YJ, Lee SP, Chang SA, Kim YJ. Age-related sex differences in the outcomes of patients with hypertrophic cardiomyopathy. PLoS One. 2022;17:e0264580. doi: 10.1371/journal.pone.0264580
3. Olivotto I, Oreziak A, Barriales-Villa R, Abraham TP, Masri A, Garcia-Pavia P, Saberi S, Lakdawala NK, Wheeler MT, Owens A, et al; EXPLORER-HCM Study Investigators. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020;396:759–769. doi: 10.1016/S0140-6736(20)31792-X
4. Hegde SM, Lester SJ, Solomon SD, Michels M, Elliott PM, Nagueh SF, Choudhury L, Zemanek D, Zwas DR, Jacoby D, et al. Effect of mavacamten on echocardiographic features in symptomatic patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2021;78:2518–2532. doi: 10.1016/j.jacc.2021.09.1381

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